Lee Lac V, Mitchell Michael L, Huang Shih-Jung, Fokin Valery V, Sharpless K Barry, Wong Chi-Huey
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 Torrey Pines Road, La Jolla, California 92037, USA.
J Am Chem Soc. 2003 Aug 13;125(32):9588-9. doi: 10.1021/ja0302836.
Potent inhibitors of fucosyltransferases, and glycosyltransferases in general, have been elusive due to the inherent barriers surrounding the family of glycosyltransfer reactions. The problems of weak substrate affinity and low catalytic proficiency of fucosyltransferase was offset by recruiting additional binding features, in this case hydrophobic interactions, to produce a high affinity inhibitor, 24, with Ki = 62 nM. The molecule was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene reactants, followed by in situ screening without product isolation.
由于糖基转移反应家族存在固有的障碍，岩藻糖基转移酶以及一般的糖基转移酶的强效抑制剂一直难以找到。通过引入额外的结合特性，在这种情况下是疏水相互作用，以产生高亲和力抑制剂24（Ki = 62 nM），抵消了岩藻糖基转移酶底物亲和力弱和催化效率低的问题。该分子是从一个由85种化合物组成的GDP-三唑文库中鉴定出来的，该文库是通过叠氮化物和乙炔反应物之间的铜（I）催化[2 + 3]环加成反应产生的，然后进行原位筛选而无需分离产物。
